PROJECT SUMMARY Major Depressive Disorder (MDD) is a leading contributor to mortality worldwide. Much of this mortality is related to depression?s deleterious effects on physical functioning, and yet the critical mechanisms linking depression to declining body function are poorly understood. MDD is characterized by significant heterogeneity in its clinical presentation, particularly with regard to vegetative symptoms that manifest as disruptions of bodily functions. Individual differences in one of these vegetative symptoms, changes in appetite, have recently been proposed to be a powerful clinical indicator of MDD?s course and treatment responsiveness. Although nearly 48% of adult MDD patients exhibit appetite decrease, and nearly 35% exhibit appetite increase, very little is known about the neurobiological differences between these groups. In a recently published study we demonstrated that depression-related appetite loss is associated with decreased activity in a region of the mid- insula shown to be critical for perceiving and integrating afferent signals about the body?s homeostatic state, a faculty otherwise known as ?interoception?. Thus, we hypothesize: (1) Depression-related appetite changes result from a failure in the insula to properly process interoceptive signals about the state of the body and integrate this information with external food cues, and (2) this underlying interoceptive deficit, which predisposes some MDD patients to appetite loss, also makes it harder for these individuals to recognize and respond to their bodily needs, thereby leaving them vulnerable to poorer long-term health outcomes. To evaluate these hypotheses, behavioral, psychophysiological, and fMRI studies will be used to assay interoceptive and food-related processes (e.g., perceiving and rating visceral sensations, perceiving food pictures) in unmedicated depressed adults with increased or decreased appetite. Specific Aim 1, which covers Project 1 in the proposed research (years 1 ? 2.5) will determine whether appetite loss in MDD is related to altered interoceptive sensitivity and interoceptive insula activity. Specific Aim 2, which covers Project 2 of the proposed work (years 2.5 - 5), will determine whether those depressed individuals who have the most severe insula dysregulation have the poorest 6-month health and mental health outcomes. The proposed research is innovative because it is the first multi-level prospective study to determine whether appetite change in MDD is directly related to how depressed individuals process interoceptive signals from their bodies. It is also impactful because Project 2 will examine the predictive validity of appetite heterogeneity with respect to MDD?s clinical outcomes. Collectively, these findings will lay the foundation for subsequent treatment studies that explore the efficacy of using appetite changes to identify depressed patients that will specifically benefit from interventions that address interoceptive deficits.